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Rachel Lamb, Susan Culican; Loss of the E3 ubiquitin ligase Phr1 is Neuroprotective in Retinal Ganglion Cells. Invest. Ophthalmol. Vis. Sci. 2013;54(15):1415.
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© ARVO (1962-2015); The Authors (2016-present)
: Phr1 is a presumed E-3 ubiquitin ligase that regulates mapping of retinal ganglion cell (RGC) axons to their target nuclei in the brain during development. Phr1 is expressed in RGCs into adulthood, but the role it plays in mature cells is not known. In invertebrate species it has been suggested that Phr1 orthologs act to constrain injury programs within cells. In order to determine the role of Phr1 following RGC injury, we compared the amount of RGC death in control and Phr1 retinal knockout mice (Phr1-rko) during normal ageing and after acute injury following axonal crush.
RGC counts: Retinas were stained with anti-Brn3a antibody and the density of Brn3a+ RGCs was determined by counting the RGC number in 24 regions of the retina, 3 peripheral and 3 central in each of 4 quadrants and dividing by the total area measured (cells/mm2). Optic nerve crush (ONC): Self-closing forceps were applied to the optic nerve of the right eye for 10 seconds to induce axotomy injury. One, three, five and ten days after ONC, RGCs from both the injured and control eyes were counted. RGC survival was expressed as the percentage of RGCs in the injured relative to the control eye in the same mouse.
Phr1 loss does not affect age related RGC loss: Over 18 months we observed a modest decline in the number of RGCs in both control and Phr1 knockout mice, but there was no effect of genotype (p>0.127). Loss of Phr1 improves RGC survival after ONC: The number of Brn3a+ RGC soma in all retinas declined in a time-dependent manner after ONC for both Phr1-rko and control mice. The amount of survival, however, differed between the genotypes. Phr1-rko RGCs had ~2-fold enhanced survival as compared to control RGCs 5 and 10 days after ONC (ANOVA p<0.001).
We have shown that RGCs deficient in the E3 ubiquitin ligase Phr1 have improved survival after ONC than wild-type controls. Our findings suggest the possibility that Phr1 acts to constrain an injury cascade that mediates endogenous neuroprotection in adult RGCs.
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